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Mechanism of Sleep-Wake Cycle

Our research goal is to clarify the mechanisms of sleep-wake regulation by prostaglandin (PG). PGD₂ is a major prostanoid produced in the central nervous system, where it promotes natural sleep; in contrast, PGE₂ induces wakefulness. PGD₂ is produced in the trabecular cells of the arachnoid membrane and choroid plexus, and is released from them to circulate in the cerebrospinal fluid. It activates the PGD₂ receptor (DP1R) to promote sleep by stimulating meningeal cells to release paracrine signaling molecules such as adenosine. The released adenosine activates adenosine A₂ᴀ receptor–expressing neurons located in the ventral region of the basal forebrain. These cells subsequently excite the sleep-active neurons in the ventrolateralpreoptic area (VLPO). The VLPO neurons then send inhibitory signals through GABAergic and galaninergic fibers to down-regulate the neuronal activity of the histaminergictuberomammillary neurons (TMN), which contribute to arousal through their histamine H1 receptor (H₁R). In contrast, PGE₂, orexin, and ciproxifan induce wakefulness when administered to the posterior hypothalamus, the location of these histaminergic neurons (Urade and Hayaishi.,Future Neurology, 2010).

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Adenosine has been demonstrated to be an inhibitory neuromodulator for sleep induction and a link between the humoral and neural mechanisms of sleep-wake regulation. Several lines of evidence indicate that both A₁R and A₂ᴀR subtypes are involved in sleep induction. The role of A₂ᴀR is predominant in sleep regulation since the selective A₂ᴀR agonist CGS21680 administered to the subarachnoid space adjacent to the basal forebrain and lateral preoptic area reliably induces a dramatic increase in non-rapid eye movement (non-REM, NREM) sleep, whereas the infusion of A₁R agonists produces weak and variable effects. Caffeine binds to A₁R and A₂ᴀR with similar high affinities and acts as an antagonist for both receptor subtypes. We used gene-manipulated mice to demonstrate that caffeine promoted wakefulness in WT and A₁R KO mice but not at all in A₂ᴀR KO mice, indicating that the arousal effect of caffeine was due to blockade of the A₂ᴀR, not the A₁R. By using selective gene deletion strategies based on the Cre/loxP technology and focal RNA interference, we reported that the A₂ᴀRs in the nucleus accumbens are responsible for the effect of caffeine on wakefulness (Lazarus et al., J. Neurosci., 2011).

A₂ᴀRs are abundantly expressed in the caudate–putamen, nucleus accumbens, and the tuberculumolfactorium, in which dopamine D₂ receptors (D₂Rs) are co-localized. To explore the role of D₂R in the sleep-wake regulation, we characterized sleep-wake profiles of D₂R KO mice under baseline conditions and after stimulation with i.p saline injection or host cage changes. Compared with WT mice, D₂R KO mice exhibited a decrease in wakefulness, increased stage transition under baseline conditions, shortened latency to NREM sleep after stimulation, an attenuated arousal effect after enhanced dopaminergic transmission, and the same sleep rebound after sleep deprivation. These findings indicate that D₂R plays an important role in arousal maintenance and is not involved in homeostatic regulation of sleep (Qu et al., J. Neurosci. 2010). Dopamine D₂R is important for the maintenance of wakefulness, whereas activation of adenosine A₂ᴀR induces potent sleep. Therefore, A₂ᴀR and D₂R are involved in sleep–wake regulation in a different manner.

A₁Rs contribute to sleep induction in a region-dependent manner. We found that inhibition of arousal neurons by adenosine through A₁R may be a way to reduce wakefulness and subsequently promote sleep. The TMN is a sole source of histaminergic arousal neurons, which express adenosine deaminase, a metabolic enzyme of adenosine. When we bilaterally injected into the rat TMN, coformycin, an adenosine deaminase inhibitor, or N6-cyclopentyladenosine (CPA), a selective A₁R agonist, NREM sleep was significantly increased in a dose-dependent manner. Immunohistochemistry showed that A₁R was moderately expressed in the histaminergic neurons of the TMN regions. In vivomicrodialysis revealed that stimulation of the TMN by injection of coformycin or CPA decreased histamine release in the frontal cortex. Induction of NREM sleep by coformycin or CPA was completely abolished by co-administration with a selective A₁R antagonist. These results indicate that adenosine in the TMN inhibits the histaminergic system via A₁R and promotes NREM sleep (Oishi, et al., 2008).

Although local administration of adenosine or an A₁R agonist into the basal forebrain and histaminergic TMN results in an increase in NREM sleep, infusion of the A₁R agonist into the lateral ventricle of mice does not alter the amounts of NREM and REM sleep, suggesting that activation of A₁R in other brain regions may cause wakefulness. Microinjection of CPA, a selective adenosine A₁R agonist, into the VLPO produced a significant reduction in NREM and REM sleep with a concomitant increase in wakefulness. Local administration of CPA into the VLPO significantly decreased the delta power density of NREM sleep during recovery sleep following 6-h sleep deprivation. Whereas, 1,3-dimethyl-8-cyclopenthylxanthine, a selective A₁R antagonist increased both NREM and REM sleep when microinjected into the VLPO. These observations suggest that activation of A₁R in the VLPO increased wakefulness; and that adenosine-mediated effects on sleep-wake cycles are site and receptor dependent (Yue et al., manuscript in preparation).

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